Hyperoxic injury complicates therapy of many acute respiratory distress syndromes. Loss of mitochondrial aconitase activity and respiration are early events in O2 toxicity. To maintain energy and survive in hyperoxia, lungs cells must increase their glucose consumption. Previous exposures which decrease respiration, including hypoxia, sublethal hyperoxia or TNF, confer pulmonary tolerance to lethal hyperoxia in rats. Some of these stimuli can upregulate lung hexokinase (HK), especially HK-II. HK phosphorylates glucose, facilitating its entry into the cell and rate-limiting glycolysis in the lung. HK also can bind to mitochondria and, thereby, could modulate their function. It is hypothesized that adaptation to oxidant stress in lung requires elevated hexokinase expression. The Specific Aims are to: 1) Determine the differential expression of hexokinase I, II, and III mRNA's and proteins in models of tolerance to, and injury by, hyperoxia in rat lungs, primate lungs, and cultured cells, including models of acute lung injury in adult baboons; 2) Define the mitochondrial association or lack thereof of these hexokinase isoforms and the expression of porin proteins to which they bind in models of acute lung injury and tolerance; and 3) Clarify the potential importance of HK-II expression in adaptation and tolerance to hyperoxia.